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Eur J Med Chem. 2016 Jun 30;116:173-186. doi: 10.1016/j.ejmech.2016.03.073. Epub 2016 Mar 30.

5-HT2 receptor affinity, docking studies and pharmacological evaluation of a series of 1,3-disubstituted thiourea derivatives.

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Chair and Department of Biochemistry, Medical University of Warsaw, 02-097, Warszawa, Poland. Electronic address:
Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, 20-031, Lublin, Poland.
Bioinformatics Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106, Warszawa, Poland.
Faculty of Chemistry, University of Warsaw, 02-093, Warszawa, Poland.
Dipartimento di Farmacia Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy.
Dipartimento di Scienze Mediche, Chirurgiche e Neuroscienze Strada delle Scotte, Università di Siena, 6 53100, Siena, Italy.
Faculty of Chemistry, Maria Curie-Sklodowska University, 20-031, Lublin, Poland.
Department of Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 02-097, Warszawa, Poland.


A series of 10 thiourea derivatives have been synthesized by the reaction of aromatic amine with a substituted aryl (compounds 1-3, 6-8) and alkylphenyl (4, 5, 9, 10) isothiocyanates. Their in vitro and in vivo pharmacological properties were studied. Among the evaluated compounds, two displayed very high affinity for the 5-HT2A receptor (1-0.043 nM and 5-0.6 nM), being selective over the 5-HT2C receptor. Derivatives 3, 5, 9, 10 by 70-89% diminished L-5-HTP-induced head twitch episodes. Compounds 1 and 5 as the 5-HT2A receptor antagonists produced a dose-dependent decrease in the number of DOI-elicited HTR. Compounds 1-5 strongly reduced amphetamine-evoked hyperactivity in rodents. In another test, 1 and 2 caused hyperthermia in mice, whereas 9 and 10 led to hypothermia. Antinociceptive and anticonvulsant properties of selected derivatives were demonstrated. Molecular docking studies using a homology model of 5-HT2A revealed a significant role of hydrogen bonds between both thiourea NH groups and Asp155/Tyr370 residues, as well as π-π interaction with Phe339.


5-HT(2A) receptor ligands; 5-HT(2C) receptor ligands; CNS activity; Docking studies; Thiourea

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